Art.-Caron (P)

The widespread abuse of cocaine, a highly addictive psychostimulant, places tremendous social, medical, and economic burdens on society. By improving our understanding of the underlying mechanisms of cocaine addiction, it may be possible to develop more effective therapeutic strategies and social policies aimed at reducing the abuse of cocaine. Cocaine inhibits the uptake of monoaminergic neurotransmitters from the extracellular space through its interaction with plasma membrane monoamine transporters1. This family of proteins, which includes the transporters for dopamine (dopamine transporter, DAT), norepinephrine (norepinephrine transporter, NET), and serotonin (serotonin transporter, SERT), acts to terminate monoaminergic transmission by rapid removal of the neurotransmitters from the synaptic cleft, back into the presynaptic terminals2. It is commonly believed that the reinforcing/addictive properties of cocaine depend on the ability of cocaine to block DAT, thereby increasing the extracellular concentration of the neurotransmitter dopamine within specific brain areas3,4. The interaction of cocaine with DAT and the resultant elevation of extracellular dopamine is correlated to its potency for inducing subjective5 and reinforcing effects6–9, thus providing a theoretical basis for its addictive properties. Therefore, disruption of the interaction between DAT and cocaine might be expected to attenuate the reinforcing effects of cocaine. Previous studies from our laboratory have shown that mice in which DAT has been genetically deleted undergo a series of profound neurochemical adaptations (DAT–/–)10,11. For example, despite a marked decrease of dopamine in the tissue, these mice exhibit higher than normal levels of extracellular dopamine and spontaneous hyperlocomotion. However, they do not display the increase in locomotor activity typically observed upon administration of high doses of cocaine10. Based on the correlation between the strength of the psychomotor stimulant properties of a drug and the strength of its reinforcing or addictive effects4, and the fact that the primary target for cocaine is absent in DAT–/– mice, cocaine would not be expected to serve as a positive reinforcer in these animals. To test this hypothesis, DAT–/– and wild-type mice were trained in a cocaine reward paradigm (cocaine i.v. self-administration), in which animals perform an operant task (lever press) in exchange for a reward (food or cocaine). Contrary to our expectation, the DAT–/– mice still self-administer cocaine even in the absence of the presumed target. Interestingly, in these mice, specific binding of a cocaine analog and c-fos gene expression in response to cocaine were observed in serotonergic brain regions. These results suggest a potential interaction of cocaine with the SERT, which might participate in the reinforcing properties of cocaine.